New analysis, which centered on glioblastoma, a uncommon kind of mind most cancers, aimed to research the potential genetic roots of the illness. The research, which has enrolled over 15,000 individuals and recognized round 350 instances of familial glioma, has found a number of genes and non-coding areas related to the situation, offering potential avenues for screening and future therapy.
A worldwide collaboration directed by a researcher from Stanford Drugs has found over 50 genes related to glioma, a uncommon mind most cancers. Whereas the vast majority of gliomas happen spontaneously, a small fraction is inherited.
In 2013, Carrie Davis Lebovich and Hadley Rierson, two sisters, discovered themselves grappling with frustration. Their father, Jon Davis, aged 69, had just lately acquired a glioblastoma analysis – a uncommon kind of mind most cancers, the identical one which had taken their grandmother’s life three a long time earlier than. Given the rarity of glioma – with solely roughly 24,000 diagnoses in the US yearly – they believed the chances of lightning hanging twice in the identical household have been slim.
“Our first query to his docs was, ‘Is that this associated to the glioblastoma that killed our grandmother?’,” Rierson recalled. “And so they all mentioned no.” Mind tumors occur randomly, the sisters have been advised. Their household’s expertise was only a coincidence.
The sisters didn’t consider them.
Carrie Davis Lebovich (left) and Hadley Davis Rierson have been satisfied that mind most cancers ran within the household when their father, Jon Davis, was recognized with the identical uncommon kind his mom died from. Researchers at Stanford Drugs proved them proper. Credit score: Connie Miller
After some dogged analysis, Lebovich and Rierson discovered Melissa Bondy, Ph.D., who was then at Baylor College of Medicine in Houston. Bondy, now the chair of the division of epidemiology and inhabitants well being on the Stanford School of Medicine, directs a world consortium referred to as Gliogene aimed toward figuring out genes concerned in familial glioma — a category of mind most cancers that features glioblastoma.
Bondy assured the sisters that, sure, regardless of what their father’s docs had advised them, a small minority of glioma instances are familial. Pinpointing the genes concerned couldn’t solely assist determine which members of affected households have an elevated threat of mind most cancers but in addition make clear the biology of the illness and drive future remedies. To take action, they wanted genetic samples from as many sufferers and their members of the family as attainable.
The sisters instantly signed on.
Now, Bondy, who’s the affiliate director for inhabitants well being sciences on the Stanford Most cancers Institute, and her Gliogene collaborators have recognized a number of genes related to familial glioma — two of that are additionally related to ovarian and colon cancers. In addition they discovered mutations in three places of the genome referred to as non-coding areas that have an effect on which genes are made into proteins.
They described their findings in an article printed April 28 in Science Advances.
“The identification of these new genes and non-coding regions is of immense value to families affected by glioma,” Bondy said. “The discovery provides the opportunity to explain to affected families why they are at risk, offer peace of mind to those who do not carry the causative mutation, and improve monitoring for those who do.”
Other senior authors of the study are Matthew Bainbridge, Ph.D., associate director of clinical genomics research at Rady Children’s Hospital San Diego, and Benjamin Deneen, Ph.D., professor at the Baylor College of Medicine. Dong-Joo Choi, Ph.D., a postdoctoral scholar at Baylor, is the lead author of the research.
Rarest cases within a rare cancer
Gliomas encompass several subtypes of brain cancers including glioblastomas, astrocytomas, and brain stem gliomas. They arise from cells in the brain called glial cells that support the brain’s neurons. Although some are slow growing and relatively treatable, the prognosis for many of these cancers is poor. According to the National Brain Tumor Society, the average survival of glioblastoma patients is eight months after diagnosis; only 6.8% are alive after five years.
Most gliomas are sporadic and seem to have no clear genetic cause. Only about 5% of gliomas are familial, afflicting two or more members of the same family. Bondy and her colleagues want to identify the genes involved in these, the rarest cases of an already rare cancer. But to do so they need to enroll as many people as possible in the Gliogene study. So far, the study has enrolled over 15,000 people and identified about 350 cases of familial glioma.
Jon Davis and his sister, Beth Karren, both died from brain cancer. Credit: Courtesy of the Davis family
Jon Davis died in July 2014, just 13 months after his glioblastoma diagnosis. In December 2014, Bondy and other members of the Gliogene consortium announced the discovery of one of the first genes associated with familial glioma — POT1. Mutations in POT1 carry an increased risk of developing glioma, the researchers found.
To find additional genes and DNA regions associated with brain cancer, Bondy and her colleagues sequenced the entire genomes of 325 people with glioma from 304 families with a history of the disease. They compared their genetic sequences with those of more than 1,000 controls without brain cancer.
They found six mutations in one gene, called HERC2, that were associated with familial glioma. The protein made from the HERC2 gene is involved in the repair of damaged DNA and the control of the cell cycle. Although these roles are shared with many other cancer-associated proteins, the HERC2 protein was not previously associated with cancer.
Two other genes — BRIP1 and POLE — that were also mutated in familial glioma cases have been associated with ovarian and colorectal cancers, respectively.
The researchers used CRISPR genetic engineering to delete several candidate genes in embryonic mice treated to develop glioma and saw that the loss of three of them — DMBT1, HP1BP3, and ZC3H7B — correlated with a decrease in survival and an increase in tumor growth in the animals.
All told, the researchers identified 54 mutations in 28 genes or non-coding regions that were associated with familial glioma in 50 out of 304 families in the Gliogene study. Many of the genes are involved in cell division, blood vessel development, and immune regulation — all factors that can contribute to tumor growth.
“This is such a rare disease,” Bondy said. “The worst part is there is currently no effective treatment for many brain tumors. My hope is that one day I can answer people who ask me ‘What is my chance of developing a glioma?’”
“Such a huge relief”
For Lebovich and Rierson, the study brings hope. Any lingering chance that their family’s brain cancers were simply coincidental vanished when their father’s sister died from a glioma in 2017. They’ve devoted their time and energy to spreading the word about familial glioma and encouraging people in affected families to join the Gliogene study.
“It couldn’t be easier or less painful to participate,” said Rierson, noting that participants simply submit a sample of saliva through the mail.
“Hadley and I had so many doors shut on us,” Lebovich said. “It felt very lonely. It was hard to get information; we were told to move on. But when we reached out to Melissa, she was on the phone with us that same day. It was such a huge relief. She has been an unbelievable partner.”
“Melissa and the Gliogene collaborators are our only hope for the future generations of our family,” Lebovich continued. “But we need people to participate in the study. The more genes we know are associated, the better you can screen potential carriers and possibly tailor treatments. But you can’t do anything if you don’t know the genes.”
Reference: “The genomic landscape of familial glioma” by Dong-Joo Choi, Georgina Armstrong, Brittney Lozzi, Prashanth Vijayaraghavan, Sharon E. Plon, Terence C. Wong, Eric Boerwinkle, Donna M. Muzny, Hsiao-Chi Chen, Richard A. Gibbs, Quinn T. Ostrom, Beatrice Melin, Benjamin Deneen, Melissa L. Bondy, The Gliogene Consortium, Genomics England Research Consortium and Matthew N. Bainbridge, 28 April 2023, Science Advances.
DOI: 10.1126/sciadv.ade2675
People who feel their families may be affected by familial glioma can learn more at gliogene.org.
Researchers from the University of Texas Health Science Center School of Public Health, Duke University, and Umea University in Sweden also contributed to the study.
The study was funded by the National Institutes of Health, the National Institute for Health Research and National Health Service England, the Wellcome Trust, Cancer Research UK, and the UK’s Medical Research Council.
